Compounds that stimulate glucose utilization and methods of use

ABSTRACT

The invention provides novel compounds of the Formula (I) that stimulate rates of glucose oxidation in myocardial cells. The invention also relates to pharmaceutical compositions comprising compounds capable of stimulation of glucose oxidation, methods for increasing glucose oxidation rates in myocardial cells, and methods of treatment of myocardial ischemia  
                 
 
     wherein  
     W is C 1 -C 6  alkyl, halogen, or argyl;  
     Cyc is C 3  or C 4  cycloalkyl;  
     p is 0-3 for Cyc being C 4  cycloalkyl and p=0-2 for Cyc being C 3  cycloalkyl;  
     Y is O, S, or NR, where R═H, alkyl or aryl;  
     X is O, S, NR, or CR 3 R 4 ;  
     Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl;  
     R 1  is H, alkyl, aryl or O;  
     R 2  is H, alkyl or aryl;  
     R 3  and R 4  are, independently, H, alkyl or aryl; and  
     n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.

[0001] This Patent Application claims priority to U.S. ProvisionalApplication S. No. 60/280,616, filed Mar. 30, 2001, the entirety ofwhich is hereby incorporated into the present application by reference.

FIELD OF THE INVENTION

[0002] The invention relates to novel compounds that stimulate rates ofglucose oxidation in myocardial cells. The invention also relates topharmaceutical compositions comprising compounds capable of stimulationof glucose oxidation, methods for increasing glucose oxidation rates inmyocardial cells, and methods of treatment of myocardial ischemia.

BACKGROUND OF THE INVENTION

[0003] Myocardial ischemia is a common clinical pathology that occurs inthe setting of angina pectoris, acute myocardial infarction, or duringcardiac surgery. Myocardial ischemia is a major clinical problem, withits complications being the major cause of mortality and morbidity inWestern society.

[0004] It has been shown that stimulating glucose oxidation both duringand following ischemia can benefit the ischemic heart. Br J Pharmacol128: 197-205, 1999, Am J Physiol 275: H1533-41, 1998. Biochimica etBiophysica Acta 1225: 191-9, 1994, Pediatric Research 34: 735-41, 1993,Journal of Biological Chemistry 270: 17513-20, 1995. Biochimica etBiophysica Acta 1301: 67-75, 1996, Am J Cardiol 80: 11A-16A, 1997,Molecular & Cellular Biochemistry 88: 175-9, 1989, Circ Res 65: 378-87,1989, Circ Res 66: 546-53, 1990, American Journal of Physiology 259:H1079-85, 1990, American Journal of Physiology 261: H1053-9, 1991, Am JPhysiol Heart Circ Physiol 280: H1762-9., 2001, J Am Coll Cardiol 36:1378-85., 2000.

[0005] To meet the high energy demands of the contracting muscle, theheart must produce a constant and plentiful supply of the free energycarrier, adenosine triphosphate (ATP). This energy is produced by themetabolism of a variety of carbon substrates, including carbohydratessuch as glucose. The metabolism of fatty acid is the other major sourceof energy for the heart.

[0006] Glucose metabolism in the heart consists of two importantpathways, namely glycolysis and glucose oxidation.

[0007] It has been shown that during ischemia (such as that produced byangina pectoris, myocardial infarction or heart surgery) the levels ofcirculating fatty acids in the plasma can be dramatically elevated. AmHeart J 128: 61-7, 1994.

[0008] As a result, during ischemia and reperfusion the heart is exposedto high levels of fatty acids, which results in the preferential use offatty acids as an oxidative substrate over glucose. It further has beenshown that this over-reliance on fatty acids as a major source of ATPcontributes to fatty acid-induced ischemic damage. This observation hassparked numerous approaches directed at switching substrate utilizationback to glucose in an attempt to protect the heart from fattyacid-induced ischemic damage. J Cardiovasc Pharmacol 31: 336-44., 1998,Am Heart J 134: 841-55., 1997, Am J Physiol 273: H2170-7., 1997,Cardiovasc Drugs Ther 14: 615-23., 2000, Cardiovasc Res 39: 381-92.,1998, Am Heart J 139: S115-9., 2000, Coron Artery Dis 12: S8-11., 2001,Am J Cardiol 82: 14K-17K., 1998, Molecular & Cellular Biochemistry 172:137-47, 1997, Circulation 95: 313-5., 1997, Gen Pharmacol 30: 639-45.,1998, Am J Cardiol 82: 42K-49K., 1998, Coron Artery Dis 12: S29-33.,2001, Coron Artery Dis 12: S3-7., 2001, J Nucl Med 38: 1515-21., 1997.Current approaches that are used to manipulate myocardial energymetabolism involve either stimulating glucose metabolism directly orindirectly (i.e., inhibiting fatty acid metabolism).

[0009] Since high fatty acid oxidation rates markedly decrease glucoseoxidation, one approach to increasing glucose oxidation is to inhibitfatty acid oxidation. This has proven effective both during andfollowing ischemia, and this pharmacological approach is starting to seeclinical use. Although a number of pharmacological agents designed toinhibit fatty acid oxidation have recently been developed, the directβ-oxidation inhibitor, trimetazidine, was the first anti-anginal agentwidely used that has a mechanism of action that can be attributed to anoptimization of energy metabolism Circulation Research. 86: 580-8, 2000.

[0010] Trimetazidine primarily acts by inhibiting fatty acid oxidation,thereby stimulating glucose oxidation in the heart.

[0011] A second clinically effective agent that switches energymetabolism from fatty acid to glucose oxidation is ranolazine. It hasbeen shown that this agent stimulates glucose oxidation secondary to aninhibition of fatty acid oxidation Circulation 93: 135-42., 1996.

[0012] The detrimental effects of fatty acids on mechanical functionduring and following ischemia are also attenuated by agents thatincrease glucose oxidation directly. Numerous experimental studies havedemonstrated that stimulation of glucose oxidation by usingdichloroacetate (DCA) following ischemia (at the expense of fatty acids)can benefit the ischemic heart. Am Heart J 134: 841-55, 1997. AlthoughDCA is an effective compound designed to stimulate glucose oxidation, ithas a short biological half-life.

[0013] Therefore, there is need to develop novel class of compounds andto identify compounds that can stimulate glucose oxidation, have longbiological life, and be effective in treatment or prevention ofmyocardial ischemia

SUMMARY OF THE INVENTION

[0014] The invention is directed to novel compounds represented by theFormula (I):

[0015] wherein

[0016] W is C₁-C₆ alkyl, halogen, or aryl;

[0017] Cyc is C₃ or C₄ cycloalkyl;

[0018] p is 0-3;

[0019] Y is O, S, or NR, where R═H, alkyl or aryl;

[0020] X is O, S, NR, or CR³R⁴;

[0021] Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl;

[0022] R¹ is H, alkyl, aryl or O;

[0023] R₂ is H, alkyl or aryl;

[0024] R³ and R⁴ are, independently, H, alkyl or aryl; and

[0025] n is an integer from 1 to 10; or a pharmaceutically acceptablesalt, ester or prodrug thereof.

[0026] The invention is further directed to methods for increasing orimproving glucose utilization in myocardial or other types of cells,tissue or organs of warm blooded animals, especially those which arecapable of high glucose metabolism (e.g., heart and other muscles). Themethod comprises treating cells, tissue or organs with substituted orunsubstituted cyclopropane carboxylic acid or cyclobutane carboxylicacid represented by the Formula (II) or their derivative compoundsaccording to Formula (I).

[0027] wherein W, Cyc and p are as defined above.

[0028] The invention if also directed to pharmaceutical compositionscomprising compounds according to the Formula (I) and suitablepharmaceutical carriers, excipients or fillers.

[0029] The invention is further directed to a method of treatment ofphysiological conditions or disorders known to be effectively treated byincreasing of cell glucose utilization. The method comprisesadministering to patients in need of such treatment effective amounts ofpharmaceutical compositions comprising substituted or unsubstitutedcyclopropane carboxylic acid or cyclobutane carboxylic acid according toFormula (II) or their derivative compounds according to the Formula (I).

[0030] The invention is further directed to kits including thepharmaceutical compositions according to the invention.

[0031] Invention methods are applicable for treating any warm bloodedanimal subjects, such as mammals, e.g., humans, primates, etc.

BRIEF DESCRIPTION OF THE DRAWINGS

[0032]FIG. 1 shows glucose oxidation in an isolated perfused working ratheart model with the indicated concentrations of cyclopropanecarboxylicacid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester (MM054).

[0033]FIG. 2 shows glucose oxidation in an isolated perfused working ratheart model with the indicated concentrations of cyclobutanecarboxylicacid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester (MM056).

[0034]FIG. 3 shows glucose oxidation in an isolated perfused working ratheart model with increasing concentrations of cyclopropanecarboxylicacid, 2-isopropoxy-ethyl ester (MM070).

[0035]FIG. 4 shows glucose oxidation in an isolated perfused working ratheart model with increasing concentrations of cyclopropanecarboxylicacid (MM001).

DETAILED DESCRIPTION OF THE INVENTION

[0036] The present invention provides novel compounds based oncyclopropane carboxylic acid or cyclobutane carboxylic acid. Thecompounds exhibit glucose oxidation stimulating activity in myocardialcells and other types of cells. The compounds according to the presentinvention are represented by the Formula (I):

[0037] wherein

[0038] W is C₁-C₆ alkyl halogen, or aryl;

[0039] Cyc is C₃ or C₄ cycloalkyl;

[0040] p is 0-3 when Cyc is C₄ cycloalkyl, and p is 0-2 when Cyc is C₃cycloalkyl;

[0041] Y is O, S, or NR , where R═H, alkyl or aryl;

[0042] X is O, S, NR, or CR³R⁴;

[0043] Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkyl carbonyl;

[0044] R¹ is H, alkyl or aryl;

[0045] R² is H, alkyl, aryl or O;

[0046] R³ and R⁴ are, independently, H, alkyl or aryl and n is aninteger from 1 to 10; or a pharmaceutically acceptable salt, ester orprodrug thereof.

[0047] As used herein, the term “alkyl” means straight or branchedalkane chain, which may be, optionally substituted with, for example,halogens, cyclic or aromatic substituents.

[0048] As used herein, the terms “aryl” or “aromatic” refer to mono- andbi-cyclic structures comprising 5-12 carbon atoms, preferably monocyclicrings containing six carbon atoms. The ring may be optionallysubstituted with alkyl, alkeny, halogen, alkoxy, or haloalkylsubstituents.

[0049] The compounds according to the present invention can be obtainedfrom substituted or unsubstituted cyclopropane carbonyl chloride orcyclobutane carbonyl chloride according to the following reactionscheme:

[0050] or their substituted derivatives

[0051] and

[0052]  where R1, R2, Y, X, Z and n are as defined above.

[0053] Preferred solvent is dichloromethane and preferred base catalystsare triethylamine and pyridine.

[0054] Reaction conditions may be varied depending on the startingmaterials and the desired end product. Optimization of the reactionconditions would be apparent for one of ordinary skill.

[0055] Preferred compounds have unsubstituted cycloalkyl rings.

[0056] In the preferred embodiments Y is O, and X is N or O, n is 1-4, pis O, R¹, R², R³ and R⁴ are hydrogens, and Z is lower alkyl, cycloalkylor phenyl; or Y is N, and X is O, n is 1 or 2, p is O, R¹, R², R³ and R⁴are hydrogens, and Z is hydrogen.

[0057] The compounds according to the present invention can beexemplified by the following compounds:

[0058] cyclopropanecarboxylic acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester;

[0059] cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylester;

[0060] (cyclobutanecarbonyl-amino)-acetic acid;

[0061] cyclopropanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester;

[0062] 2-(cyclopropanecarbonyl-amino)-propionic acid;

[0063] cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester;

[0064] cyclobutanecarboxylic acid, 2-(2-butoxy-ethoxy)-ethyl ester;

[0065] cyclobutanecarboxylic acid, 2-(2-ethoxy-ethoxy)-ethyl ester;

[0066] cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethylester;

[0067] cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethylester;

[0068] cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethoxy)-ethylester;

[0069] cyclobutanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester;

[0070] cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;

[0071] cyclobutanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester;

[0072] cyclopropanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;

[0073] cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester;

[0074] cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester;

[0075] cyclobutanecarboxylic acid 2-isopropoxy-ethyl ester;

[0076] cyclopropanecarboxylic acid,2-(2-cyclobutanecarbonyloxy-ethoxy)-ethyl ester;

[0077] cyclopropanecarboxylic acid,2-[2-(2-cyclopropanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester; and

[0078] cyclobutanecarboxylic acid,2-[2-(2-cyclobutanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester.

[0079] The invention further provides a method for increasing the rateof glucose oxidation and improving glucose utilization in myocardial andother cells, tissue or organs of humans and animals. It has beendiscovered that substituted or unsubstituted cyclopropanecarboxylicacid, cyclopropanecarboxylic acid represented by the Formula (II) andcyclobutanecarboxylic acid derivatives, such as cyclopropanecarboxylicacid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester andcyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl esterand other compounds represented by the Formula (I) can increase glucoseutilization in myocardial an other types of cells, tissue or organs ofwarm blooded animals, including humans.

[0080] wherein W is C₁-C₆alkyl, halogen, or aryl;

[0081] Cyc is C₃ or C₄ cycloalkyl; and

[0082] p is 0-3 when Cyc is C₄ cycloalkyl, or p is 0-2 when Cyc is C₃cycloalkyl;

[0083] The method according to the present invention comprises treatingcells, tissue or organs of the animal with at least one compoundrepresented by Formula (I) or Formula (II). The compounds of the Formula(I) or Formula (II) can be delivered to the cells, tissues or organs byoral administration, injection or infusion, etc., of the compounds ofthe Formula (I) or (II) to the animals.

[0084] The invention further provides pharmaceutical compositionscomprising, as its active component, at least one compound according tothe Formulas (I) or (II), their pharmaceutically acceptable salt, esteror prodrugs. Pharmaceutical compositions comprising more than onecompound according to the Formulas (I) or (II), their various mixturesand combinations are also within the scope of the present invention.

[0085] Pharmaceutical compositions or formulations include carriers andexcipients compatible with oral, intravenous, intramuscular,intraarterial, intracranial, and intracavity administration.Pharmaceutical formulations further include colloidal dispersionsystems, or lipid formulations (e.g., cationic or anionic lipids),micelles, microbeads, etc.

[0086] Pharmaceutical compositions of the invention includepharmaceutically acceptable and physiologically acceptable carriers,diluents or excipients. Examples of suitable carriers, diluents andexcipients include solvents (aqueous or non-aqueous), solutions,emulsions, dispersion media, coatings, isotonic and absorption promotingor delaying agents, compatible with pharmaceutical administration, andother commonly used carriers known in the art.

[0087] Compositions can also include carriers to protect the compositionagainst rapid degradation or elimination from the body, such as acontrolled release formulation, including implants and microencapsulateddelivery systems. For example, a time delay material such as glycerylmonostearate or glyceryl stearate alone, or in combination with a wax,may be employed.

[0088] Pharmaceutical compositions can be formulated to be compatiblewith a particular route of administration. For oral administration, acomposition can be incorporated with excipients and used in the form oftablets, pills or capsules, e.g., gelatin capsules. Pharmaceuticallycompatible binding agents, and/or adjuvant materials can be included inoral formulations. The tablets, pills, capsules, etc., can contain anyof the following ingredients, or similar compounds: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; or a flavoring orsweetening agent.

[0089] Pharmaceutical compositions for parenteral, intradermal, orsubcutaneous administration can include a sterile diluent, such aswater, saline solution, fixed oils, polyethylene glycols, glycerine,propylene glycol or other synthetic solvents; antibacterial agents suchas benzyl alcohol or methyl parabens; antioxidants such as ascorbic acidor sodium bisulfite; chelating agents such as ethylenediaminetetraaceticacid; buffers such as acetates, citrates or phosphates and agents forthe adjustment of tonicity such as sodium chloride or dextrose.

[0090] Pharmaceutical compositions for injection include sterile aqueoussolutions (where water-soluble) or dispersions and sterile powders forthe extemporaneous preparation of sterile injectable solutions ordispersion. For intravenous administration, suitable carriers includephysiological saline, bacteriostatic water, Cremophor EL™ (BASF,Parsippany, N.J.) or phosphate buffered saline (PBS). Antibacterial andantifungal agents include, for example, parabens, chlorobutanol, phenol,ascorbic acid and thimerosal. Isotonic agents, for example, sugars,polyalcohols such as manitol, sorbitol, sodium chloride may be includedin the composition. Including an agent which delays absorption, forexample, aluminum monostearate and gelatin can prolong absorption ofinjectable compositions.

[0091] The pharmaceutical formulations can be packaged in dosage unitform for ease of administration and uniformity of dosage. Dosage unitform as used herein refers to physically discrete units suited asunitary dosages for the subject to be treated; each unit containing apredetermined quantity of active compound calculated to produce thedesired therapeutic effect in association with the pharmaceuticalcarrier or excipient.

[0092] The compositions can be administered by any route compatible witha desired outcome. Thus, routes of administration include oral (e.g.,ingestion or inhalation), intraperitoneal, intradermal, subcutaneous,intravenous, intraarterial, intracavity, intracranial, and parenteral.The compositions can also be administered using implants andmicroencapsulated delivery systems.

[0093] Compositions, including pharmaceutical formulations can furtherinclude particles or a polymeric substance, such as polyesters,polyamine acids, hydrogel, polyvinyl pyrrolidone, ethylene-vinylacetate,methylcellulose, carboxymethylcellulose, protamine sulfate, orlactide/glycolide copolymers, polylactide/glycolide copolymers, orethylenevinylacetate copolymers. Cyclopropanecarboxylic acid,cyclopropanecarboxylic acid and derivatives and modified forms thereofcan be entrapped in microcapsules, for example, by the use ofhydroxymethylcellulose or gelatin-microcapsules, or poly(methylmethacrolate) microcapsules, respectively, or in a colloid drugdelivery system.

[0094] In instances where cell, tissue or organ targeting is desired, acomposition of the invention can of course be delivered to the targetcell, organ or tissue by injection or infusion or the like. Targetingcan be achieved by injection or infusion in practicing the methods ofthe invention. Targeting can also be achieved by using proteins thatbind to a cell surface protein (e.g., receptor or matrix protein)present on the cell or population of cell types. For example, antibodiesor antibody fragments (e.g., Fab region) that bind to a cell surfaceprotein can be included in the delivery systems in order to facilitatecell, tissue or organ targeting. Viral coat proteins that bindparticular cell surface proteins can be used for targeting. For example,naturally occurring or synthetic (e.g. recombinant) retroviral envelopeproteins with known cell surface protein binding specificity can beemployed in the liposomes in order to intracytoplasmically delivercyclopropanecarboxylic acid, cyclopropanecarboxylic acid and derivativesand modified forms thereof into target cells, tissue or organs. Thus,delivery vehicles, including colloidal dispersion systems, can be madeto have a protein coat in order to facilitate targeting orintracytoplasmic delivery of cyclopropanecarboxylic acid,cyclopropanecarboxylic acid and derivatives and modified forms thereof.

[0095] The invention further provides a method for prophylactic andtherapeutic treatments of various physiological condition or disordertreatable by increasing or improving glucose utilization in cells,tissue or organs of a patient by administering to the patient in need ofsuch treatment, effective amounts of pharmaceutical compositionscomprising substituted or unsubstituted cyclopropanecarboxylic acid,cyclopropanecarboxylic acid and cyclobutanecarboxylic acid derivativecompounds represented by the Formulas (I) and (II).

[0096] Disorders or conditions that can be treated with a methodaccording to the present invention include, for example,ischemic/reperfusion injury, post myocardial infarction, angina, heartfailure, a cardiomyopathy, peripheral vascular disease, diabetes, andlactic acidosis, or symptoms or side effects associated with heartsurgery (e.g., open heart surgery, bypass surgery, heart transplant).

[0097] The method according to the present invention includesadministering a pharmaceutical compositions comprising effective amountsof substituted or unsubstituted cyclopropanecarboxylic acid,cyclopropanecarboxylic acid and cyclobutanecarboxylic acid derivativecompounds represented by the Formulas (I) and (II) in a single dailydose, or the total daily dosage may be administered in divided dosesseveral times daily. Furthermore, the pharmaceutical compositions may beadministered as a single dose or over a period of time.

[0098] Patients that can be treated with the method according to thepresent invention include all known kind of mammals, including non humanprimates (apes, gibbons, chimpanzees, orangutans, macaques), companionanimals (dogs and cats), farm animals (horses, cows, goats, sheep,pigs), experimental animals (mouse, rat, rabbit, guinea pig), andhumans.

[0099] The dosage regiment utilizing the pharmaceutical compositionsaccording to the present invention is selected based on various factorssuch as type of physiological condition to be treated, age, weight, sexof the patient, severity of the conditions to be treated, the route ofadministration, and particular compound contained in the pharmaceuticalcomposition. A physician or veterinarian of ordinary skill can readilydetermine and prescribed the effective amount of the pharmaceuticalcomposition to prevent or to treat the specific physiological condition.

[0100] The daily dosage may be varied over wide range and can be suchthat the amount of the active compound selected from substituted orunsubstituted cyclopropanecarboxylic acid, cyclopropanecarboxylic acidand cyclobutanecarboxylic acid derivative compounds represented by theFormulas (I) and/or Formula (II) is sufficient to increase glucoseutilizationin a cell, tissue or organ of a warm blooded animal and toachieve the desired effect of alleviating or preventing fattyacid-induced ischemic damage.

[0101] The invention provides kits containing substituted orunsubstituted cyclopropanecarboxylic acid, cyclopropanecarboxylic acidand derivatives and modified forms thereof represented by the Formulas(I) and Formula (II), including pharmaceutical formulations, packagedinto a suitable set. A kit typically includes a label or packaginginsert including instructions for use, in vitro, in vivo, or ex vivo, ofthe components therein.

[0102] The term “packaging material” refers to a physical structurehousing the components of the kit, such as cyclopropanecarboxylic acid,cyclopropanecarboxylic acid or derivatives or modified forms thereof.The packaging material can maintain the components sterilely, and can bemade of material commonly used for such purposes (e.g., paper,corrugated fiber, glass, plastic, foil, ampules, etc.). The label orpackaging insert can include appropriate written instructions, forexample, practicing a method of the invention.

[0103] Kits of the invention therefore can additionally includeinstructions for using the kit components in a method of the invention.Instructions can include instructions for practicing any of the methodsof the invention described herein. Thus, for example, a kit can includea cyclopropanecarboxylic acid, cyclopropanecarboxylic acid or aderivative or modified form thereof in a pharmaceutical formulation in acontainer, pack, or dispenser together with instructions foradministration to a human subject. Instructions may additionally includeindications of a satisfactory clinical endpoint or any adverse symptomsthat may occur, or any additional information required by the Food andDrug Administration for use in humans.

[0104] A kit may include instructions for increasing or improvingglucose utilization in vitro, ex vivo or in vivo. In other embodiments,a kit includes instructions for treating a disorder associated withdeficient or inefficient glucose utilization. In one aspect, theinstructions comprise instructions for treating a subject having or atrisk of having ischemic/reperfusion injury, post myocardial infarction,angina, heart failure, a cardiomyopathy, peripheral vascular disease,diabetes, or lactic acidosis. In another aspect, the instructionscomprise instructions for treating a subject having or at risk of havingheart surgery (e.g., open heart surgery, bypass surgery, hearttransplant and angioplasty).

[0105] The instructions may be on “printed matter,” e.g., on paper orcardboard within the kit, or on a label affixed to the kit or packagingmaterial, or attached to a vial or tube containing a component of thekit. Instructions may additionally be included on a computer readablemedium, such as a disk (floppy diskette or hard disk), optical CD suchas CD- or DVD-ROM/RAM, magnetic tape, electrical storage media such asRAM and ROM and hybrids of these such as magnetic/optical storage media.

[0106] Kits can additionally include a buffering agent, a preservative,or a stabilizing agent. Each component of the kit can be enclosed withinan individual container and all of the various containers can be withina single package.

[0107] The present invention is further illustrated in the followingexamples wherein all parts, percentages, and ratios are in equivalents,all temperatures are in ° C., and all pressures are atmospheric unlessotherwise indicated:

EXAMPLE 1 Preparation of Cyclopropanecarboxylic Acid,2-[2-(2-Methoxy-ethoxy)-ethoxy]-ethyl Ester

[0108]

[0109] Triethylene glycol monomethyl ether (1.1 eq, 5.26 mmol, 0.84 ml),triethylamine (1.1 eq, 5.26 mmol, 0.73 ml) was taken in a 10 ml roundbottom flask and dichloromethane (3 ml) was added. This mixture wascooled to 0° C. and then cyclopropanecarbonyl chloride (4.78 mmol, 0.5g, 0.43 ml) was added in a dropwise fashion maintaining the temperatureat 0° C. with constant stirring.

[0110] A yellowish-orange solid was observed after some time. Stirringwas continued for 1 hr at 0° C. The reaction was monitored by thin layerchromatography, and then quenched with saturated ammonium chloridesolution. It was then transferred to a separatory funnel, washed with 5%sodium bicarbonate (2×5 ml), 1:1 hydrochloric acid (2×5 ml) and thenwith brine (5 ml). The dichloromethane layer was separated from theaqueous layer, dried over anhydrous sodium sulphate, filtered, andevaporated in vacuo to give the title product as a pale yellow liquid.Purification was attempted by flash chromatography and vacuumdistillation (b.p.=144° C., 3.0 mm of Hg) which afforded the pureproduct as a colorless liquid (527.0 mg, 48%).

[0111] Thus obtained compound was characterized by ¹H NMR and mass spec.¹H NMR (300 MHz, CDCl₃) 8 4.2 (m, 2H), 3.68 (m, 2H), 3.64 (m, 6H), 3.52(m, 2H), 3H), 1.62 (m, 1H), 0.99 (m, 2H), 0.84 (m, 2H); MS (ES, MNa⁺)Calcd for C₁₁H₂₀O₅Na 255.11, found 255.1.

EXAMPLE 2 Preparation of Cyclobutanoylglycine (or(Cyclobutanecarbonyl-amino)-acetic Acid)

[0112]

[0113] Methyl ester glycine hydrochloride (1 eq, 2.39 mmol, 300 mg),pyridine (2 eq, 4.78 mmol, 0.39 ml), was suspended in (5 ml) ofdichloromethane followed by addition of DMAP (1.5 eq, 218.5 mg) in oneportion and the reaction was stirred for 30 min at room temperature.After 30 min, cyclobutanecarbonyl chloride (2 eq, 4.77 mmol, 0.54 ml)was added slowly and the reaction mixture was stirred for 4 hrs at roomtemperature. The solvent was evaporated in vacuo and the residueextracted with ethyl acetate. The ethyl acetate layer was dried andconcentrated to dryness. The crude material obtained was purified byflash chromatography to yield pure compound A (358 mg, 87%).

[0114] To a solution of A in (6 ml) THF, was added lithium hydroxide(1.1 eq, 2.3 mmol, 2.3 ml, 1M) at room temperature and the reactionmixture was stirred for 1.5 hrs. The reaction mixture was thenconcentrated in vacuo and acidified to pH=3 with 2N HCl. The crudeproduct was then extracted with ethyl acetate and purified byrecrystallization, using ethyl acetate/hexane mixture. The productobtained after recrystallization was further purified by flashchromatography and again recrystallization to give the title compound Bas a white solid (196 mg, 59%).

[0115] Thus obtained compound was characterized by ¹H NMR and mass spec.¹HNMR (300 MHz, CD₃0D) 5 3.87 (s, 2H), 3.14 (quintet, 1H), 1.84-2.2 (m,6H); HRMS (ES, MNa⁺) Calcd for C₇H₁₁NO₃Na 180.06311 found 180.06290.

EXAMPLE 3 Preparation of Cyclobutanecarboxylic Acid,2-[2-(2-Methoxy-ethoxy)-ethoxy]-ethyl Ester

[0116]

[0117] Triethylene glycol monomethyl ether (1.1 eq, 4.64 mmol, 0.74 ml),triethylamine (1.1 eq, 4.64 mmol, 0.65 ml) was taken in a 25 ml roundbottom flask and dichloromethane (3 ml) was added. This mixture wascooled to 0° C. and then cyclobutanecarbonyl chloride (4.22 mmol, 0.5 g,0.48 ml) was added in a dropwise fashion maintaining the temperature at0° C. with constant stirring (Vigorous reaction).

[0118] A pink colored solution was observed after some time. An extra 4ml of dichoromethane was added to maintain proper stirring (reactionmixture becomes thick). Stirring was continued for 1 hr at 0° C. Thereaction was monitored by thin layer chromatography and then quenchedwith saturated ammonium chloride solution. It was then transferred to aseparatory funnel, washed with 5% sodium bicarbonate (2×5 ml), 1:1hydrochloric acid (2×5 ml) and then with brine (5 ml). Thedichloromethane layer was separated from the aqueous layer, dried overanhydrous sodium sulphate, filtered, and evaporated in vacuo to give thetitle product as a pale yellowish-pink liquid. The liquid was purifiedby flash chromatography and vacuum distillation (b.p.=189° C., 3.0 mm ofHg) to yield the pure product as a colorless liquid (679.6 mg, 65.34%).

[0119] The product was characterized by ¹H NMR and mass spec. ¹HNMR (300MHz, CDCl₃) 6 4.18 (m, 2H), 3.4 (m, 2H), 3.6 (m, 6H), 3.5 (m, 2H), 3.32(s, 3H), 3.1 (quintet, 1H), 2.2 (m, 4H), 1.86 (m, 2H); MS (ES, MNa⁺)Calcd for C₁₂H₂₂O₅Na 269.13, found 269.1.

EXAMPLES 4, 6-16, and 18-22 Preparation of Cyclopropanecarboxylic Acidand of Cyclobutanecarboxylic Acid Derivatives

[0120]

[0121] where, R=

[0122] R¹—OH=Corresponding Alcohols

[0123] Base=Triethylamine or Pyridine

[0124] Solvent=Dichloromethane

[0125] The procedures of Example 1 and Example 3 were followed forpreparation cyclopropanecarboxylic acid and of cyclobutanecarboxylicacid derivatives respectively, except that various starting alcoholswere used in place of triethylene glycol monomethyl ether. All obtainedcompounds were characterized by ¹H NMR and mass spec. The results aresummarized in TABLE 1.

EXAMPLE 5 Preparation of Cyclopropanoylalanine

[0126]

[0127] The procedure of Example 2 was followed except that 2.5equivalents of pyridine was used instead of 2 equivalents,cyclopropanecarbonyl chloride was used in place ofcyclobutanecarbonylchloride and methyl ester alanine hydrochloride wasused in palce of methyl ester glycine hydrochloride.

[0128] Purified compound B (321 mg, 87%) was characterized by ¹H NMR andmass spec. ¹HNMR (300 MHz, CD₃OD) δ 8.25 (br s, 1H), 4.38 (m, 1H), 3.25(s, 1H), 1.64 (m, 1H), 1.39 (dd, 3H), 0.7-0.9 (m, 4H); HRMS (ES, M)Calcd for C₇H₁₂NO₃ 158.08117, found 158.08123.

EXAMPLE 17 Preparation of Cyclopropanecarboxylic Acid 2-isopropoxy-ethylEster

[0129]

[0130] 2-Isopropoxy-ethanol (1.1 eq, 5.26 mmol, 0.55 g, 0.61 ml),Pyridine (1.1 eq, 5.26 mmol, 0.42 g, 0.43 ml) was taken in a 25 ml roundbottom flask and dichloromethane (6 ml) was added. This mixture wascooled to 0° C. and then cyclopropanecarbonyl chloride (4.78 mmol, 0.5g, 0.43 ml) was added in a dropwise fashion maintaining the temperatureat 0° C. with constant stirring.

[0131] An orange-yellow colored solution was observed after sometime. Anextra 2 ml of dichoromethane was added to maintain proper stirring(reaction mixture becomes thick). Stirring was continued for 1 hr at 0°C. The reaction was monitored by thin layer chromatography and thenquenched with saturated ammonium chloride solution. It was thentransferred to a separatory funnel, washed with 5% sodium bicarbonate(2×5 ml), 1:1 Hydrochloric acid (2×5 ml), and then with brine (5 ml).The dichloromethane layer was separated from the aqueous layer, driedover anhydrous magnesium sulphate, filtered, and evaporated in vacuo togive the title product as a pale yellowish-orange liquid. Purificationwas attempted by flash chromatography and vacuum distillation (b.p.=33°C., 2.9 mm of Hg) which afforded the pure product as a colorless liquid(630.2 mg, 76.40%).

[0132] Characterization of the resulting compound was done by ¹H NMR andmass spec. ¹HNMR (400 MHz, CDCl₃) δ 4.2 (m, 2H), 3.6 (m, 3H), 1.65 (m,1H), 1.15 (d, 6H), 1.0 (m, 2H), 0.85 (m, 2H); MS (ES, MNa⁺) Calcd forC₉H₁₆O₃Na 195.09, found 195.0 TABLE 1 Starting Starting R′- MolecularCarbonyl YH Example Compound Weight Chloride compound 1 MM054

232.28 P* 2-[2-(2- Methoxy- ethoxy)- ethoxy]-ethanol 2 MM055

157.17 B** Methyl ester glycine hydrochloride-- -(Amino Acid) 3 MM056

246.31 B 2-[2-(2- Methoxy- ethoxy)- ethoxy]-ethanol 4 MM057

264.31 P 2-(2- Benzyloxy- ethoxy)-ethanol 5 MM058

157.17 P Methyl ester alanine hydrochloride (Amino Acid) 6 MM059

278.34 B 2-(2- Benzyloxy ethoxy)-ethanol 7 MM060

244.32 B 2-(2-Butoxy- ethoxy)-ethanol 8 MM061

216.27 B 2-(2-ethoxy- ethoxy)-ethanol 9 MM062

201.26 P 2-(2- dimethylamino- ethoxy)- ethanol 10 MM063

215.29 B 2-(2- dimethylamino- ethoxy)- ethanol 11 MM064

258.35 P 2-(2-hexyloxy- ethoxy)-ethanol 12 MM065

272.39 B 2-(2-hexyloxy- ethoxy)-ethanol 13 MM066

188.23 P 2-(2-methoxy- ethoxy)-ethanol 14 MM067

202.25 B 2-(2-methoxy- ethoxy)-ethanol 15 MM068

158.20 P 2-(2-ethoxy- ethoxy)-ethanol 16 MM069

172.23 B 2-(2-ethoxy- ethoxy)-ethanol 17 MM070

172.23 P 2-Isopropoxy- ethanol 18 MM071

186.25 B 2-Isopropoxy- ethanol 19 MM072

242.27 P 2-(2-Hydroxy- ethoxy)-ethanol 20 MM073

270.32 B 2-(2-Hydroxy- ethoxy)-ethanol 21 MM074

286.32 P 2-[2-(2- Hydroxy- ethoxy)- ethoxy]-ethanol 22 MM075

314.37 B 2-[2-(2- Hydroxy- ethoxy)- ethoxy]-ethanol

EXAMPLE 23

[0133] Glucose oxidation stimulation in untreated myocardium cells andmyocardium cells treated with cyclopropanecarboxylic acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester. Rat hearts were cannulatedfor isolated working heart 60 min aerobic perfusions as described in JPharmacol Exp Ther. 1993; 264:135-144, the entire disclosure of which isincorporated herein by reference.

[0134] Male Sprague-Dawley rats (0.3-0.35 kg) were anesthetized withpentobarbital sodium (60 mg/kg IP) and hearts were quickly excised, theaorta was cannulated and a retrograde perfusion at 37° C. was initiatedat a hydrostatic pressure of 60 mm Hg. Hearts were trimmed of excesstissue, and the pulmonary artery and the opening to the left atrium werethen cannulated. After 15 min of Langendorff perfusion, hearts wereswitched to the working mode by clamping the aortic inflow line from theLangendorff reservoir and opening the left atrial inflow line. Theperfusate was delivered from an oxygenator into the left atrium at aconstant preload pressure of 11 mm Hg. Perfusate was ejected fromspontaneously beating hearts into a compliance chamber (containing 1 mlof air) and into the aortic outflow line. The afterload was set at ahydrostatic pressure of 80 mm Hg. All working hearts were perfused withKrebs'-Henseleit solution containing calcium 2.5 mmol/L, glucose 5.5mmol/L, 3% bovine serum albumin (fatty acid free, initial fractionationby heat shock, Sigma), and with 1.2 mmol/L palmitate. Palmitate wasbound to the albumin as described in J Bio Chem. 1992; 267:3825-3831,the entire disclosure of which is incorporated herein by reference.

[0135] The perfusate was recirculated, and pH was adjusted to 7.4 bybubbling with a mixture containing 95% O₂ and 5% CO₂.

[0136] Spontaneously beating hearts were used in all perfusions. Heartrate and aortic pressure were measured with a Biopac Systems Inc. bloodpressure transducer connected to the aortic outflow line. Cardiac outputand aortic flow were measured with Transonic T206 ultrasonic flow probesin the preload and afterload lines, respectively. Coronary flow wascalculated as the difference between cardiac output and aortic flow.Cardiac work was calculated as the product of systolic pressure andcardiac output.

[0137] Measurement of Glucose Oxidation: Glucose oxidation was measuredsimultaneously by perfusing hearts with [U-¹⁴C] glucose according to theprocedures discussed in Saddik M, et al., J Bio Chem. 1992;267:3825-3831. The entire disclosure of this reference is incorporatedherein by reference. The total myocardial ¹⁴CO₂ production wasdetermined at 10-min intervals from the 60-min aerobic period. Glucoseoxidation rates were determined by quantitative measurement of ¹⁴CO₂production as described in Barbour R L, et al., Biochemistry. 1984;1923:6503-6062. The entire disclosure of this reference is incorporatedherein by reference. ¹⁴CO₂ production for the control group werecompared with the ¹⁴CO₂ production for the group treated withcyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylester. Results are shown on FIG. 1 and TABLE 2.

EXAMPLE 25

[0138] Glucose oxidation stimulation in myocardium cells treated withcyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester.

[0139] The procedure of Example 23 for was followed except thatcyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl esterin 1 μM, 10 μM, 100 μM and 1000 μM amounts was added to the buffer inplace of the cyclopropanecarboxylic acid,2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester. The results are illustratedin FIG. 2 and TABLE 2.

EXAMPLE 26

[0140] Glucose oxidation stimulation in myocardium cells treated withcyclopropanecarboxylic acid, 2-isopropoxy ethyl ester.

[0141] The procedure of Example 23 was followed except thatcyclopropanecarboxylic acid, 2-isopropoxy-ethyl ester in 1 μM, 10 μM,100 μM and 1000 μM amounts was added to the buffer in place of thecyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxyl]-ethylester. The results are illustrated in FIG. 3 and TABLE 2.

EXAMPLES 24, 27-41 and 43

[0142] Glucose oxidation stimulation in myocardium cells treated withvarious cyclopropanecarboxylic acid and cyclobutanecarboxylic acidderivatives.

[0143] The procedure of Example 23 was followed except that variouscyclobutanecarboxylic acid derivatives, cyclopropanecarboxylic acidderivatives and cyclobutanecarboxylic acid in the amounts of 100 μM or1000 μM was added to the buffer in place of the cyclopropanecarboxylicacid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester. The results areillustrated in TABLE 2.

EXAMPLE 42

[0144] Glucose oxidation stimulation in myocardium cells treated withcyclopropanecarboxylic acid.

[0145] The procedure of Example 23 was followed except thatcyclobutanecarboxylic acid the amounts of 0.001 μM, 0.01 μM, 01 μM, 1μM, 10 μM, and 100 μM was added to the buffer in place of thecyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethylester. The results are illustrated in FIG. 4 and TABLE 2. TABLE 2Screening Glucose Concentration Oxidation Example Compound (μM) (% abovecontrol) 23 MM054

100 102% 24 MM055

1000 μM  58% 25 MM056.

100 μM 54% 26 MM057

100 μM 104% 27 MM058

1000 μM  40% 28 MM059

100 μM 68% 29 MM060

100 μM 65% 30 MM062

100 μM 77% 31 MM063

100 μM 41% 32 MM064

100 μM 83% 33 MM065

100 μM 0% 34 MM066

100 μM 20% 35 MM067

100 μM 50% 36 MM068

100 μM 416% 37 MM069

100 μM 162% 38 MM070

100 μM 208% 40 MM071

100 μM 97% 41 MM072

100 μM 97% 42 MM001

1000 μM  121% 43 MM002

1000 μM  239%

[0146] A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.

What is claimed is:
 1. A compound represented by formula (I):

wherein W is C₁-C₆ alkyl, halogen, or aryl; Cyc is C₃ or C₄ cycloalkyl; p is 0-3 for Cyc being C₄ cycloalkyl, or p=0-2 for Cyc being C₃ cycloalkyl; Y is O, S, or NR , where R═H, alkyl or aryl; X is O, S, NR, or CR³R⁴. Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl; R¹ is H, alkyl, aryl or O; R² is H, alkyl or aryl; R³ and R⁴ are, independently, H, alkyl or aryl; and n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.
 2. The compound as claimed in claim 1, wherein p is
 0. 3. The compound as claimed in claim 2, wherein Y is O; X is N or O; R1, R2, R3 and R4 are hydrogens; n is 1-4; and Z is lower alkyl, cycloalkyl or phenyl.
 4. The compound as claimed in claim 2, wherein Y is N; X is O; R11, R2, R3 and R4 are hydrogens; n is 1 or 2; and Z is hydrogen.
 5. The compound as claimed in claim 2, wherein said compound is selected from cyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester; cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester; (cyclobutanecarbonyl-amino)-acetic acid; cyclopropanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester; 2-(cyclopropanecarbonyl-amino)-propionic acid; cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid, 2-(2-butoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid, 2-(2-ethoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester; cyclobutanecarboxylic acid 2-isopropoxy-ethyl ester; cyclopropanecarboxylic acid, 2-(2-cyclobutanecarbonyloxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid, 2-[2-(2-cyclopropanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester; and cyclobutanecarboxylic acid, 2-[2-(2-cyclobutanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester.
 6. A pharmaceutical composition comprising at least one compound represented by Formula (I), or Formula (II):

wherein W is C₁-C₆ alkyl, halogen, or aryl; Cyc is C₃ or C₄ cycloalkyl; p is 0-3 for Cyc being C₄ cycloalkyl, or p=0-2 for Cyc being C₃ cycloalkyl; Y is O, S, or NR, where R═H, alkyl or aryl; X is O, S, NR, or CR³R⁴; Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl; R¹ is H, alkyl, aryl or O; R² is H, alkyl or aryl; R³ and R⁴ are, independently, H, alkyl or aryl; and n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof; and a pharmaceutically acceptable carrier, diluent, excipient or mixtures thereof.
 7. The pharmaceutical composition as claimed in claim 6, wherein said compound is represented by Formula (I), and wherein p=0; Y is O; X is N or O; R1, R2, R3 and R4 are hydrogens; n is 1-4; and Z is lower alkyl, cycloalkyl or phenyl.
 8. The pharmaceutical composition as claimed in claim 6, wherein said compound is represented by the Formula (I), and wherein p=0; Y is N; X is O; R1, R2, R3 and R4 are hydrogens; n is 1 or 2; and Z is hydrogen.
 9. The pharmaceutical composition as claimed in claim 6, wherein said compound is represented by the Formula (II), wherein p=0.
 10. The pharmaceutical compositions as claimed in claim 6, wherein said composition is in the form of tablets, pills, capsules, aqueous solutions, or sterile suspensions or solutions.
 11. The pharmaceutical composition according to claim 6, wherein said at least one compound is selected from the group consisting of cyclopropanecarboxylic acid; cyclobutanecarboxylic acid; cyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester; cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester; (cyclobutanecarbonyl-amino)-acetic acid; cyclopropanecarboxylic acid, 2-(2-benzyloxy-ethoxy)-ethyl ester; 2-(cyclopropanecarbonyl-amino)-propionic acid; cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-butoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester; cyclobutanecarboxylic acid 2-isopropoxy-ethyl ester; cyclopropanecarboxylic acid, 2-(2-cyclobutanecarbonyloxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid, 2-[2-(2-cyclopropanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester; and cyclobutanecarboxylic acid, 2-[2-(2-cyclobutanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester.
 12. A method for increasing glucose utilization in a cell, tissue or organ of a warm blooded animal comprising treating said cell, tissue or organ with at least one compound represented by Formula (I) or Formula (II)

wherein W is C₁-C₆ alkyl, halogen, or aryl; Cyc is C₃ or C₄ cycloalkyl; p is 0-3 for Cyc being C₄ cycloalkyl, or p=0-2 for Cyc being C₃ cycloalkyl; Y is O, S, or NR , where R═H, alkyl or aryl; X is O, S, NR, or CR³R⁴; Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl; R¹ is H, alkyl, aryl or O; R₂ is H, alkyl or aryl; R³ and R⁴ are, independently, H, alkyl or aryl; and n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.
 13. The method as claimed in claim 12, wherein said compound is represented by Formula (I), and wherein p=0; Y is O; X is N or O; R1, R2, R3 and R4 are hydrogens; n is 1-4; and Z is lower alkyl, cycloalkyl or phenyl.
 14. The method as claimed in claim 12, wherein said compound is represented by Formula (I), and wherein p=0; Y is N; X is O; R1, R2, R3 and R4 are hydrogens; n is 1 or 2; and Z is hydrogen.
 15. The method as claimed in claim 12, wherein said compound is represented by Formula (II), wherein p=0.
 16. The method as claimed in claim 12, wherein said organ is heart.
 17. The method as claimed in claim 12, wherein said cell is a myocardial cells.
 18. The method as claimed in claim 12, wherein said at least one compound is selected from the group consisting of cyclopropanecarboxylic acid; cyclobutanecarboxylic acid; cyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester; cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester; (cyclobutanecarbonyl-amino)-acetic acid; cyclopropanecarboxylic acid, 2-(2-benzyloxy-ethoxy)-ethyl ester; 2-(cyclopropanecarbonyl-amino)-propionic acid; cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-butoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester; cyclobutanecarboxylic acid 2-isopropoxy-ethyl ester; cyclopropanecarboxylic acid, 2-(2-cyclobutanecarbonyloxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid, 2-[2-(2-cyclopropanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester; and cyclobutanecarboxylic acid, 2-[2-(2-cyclobutanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester.
 19. A method for treatment of physiological conditions or disorders treatable by increasing glucose utilization comprising: administering to a patient in need of such treatment, effective amounts of a pharmaceutical composition comprising at least one compound represented by Formula (I) or Formula (II)

 wherein W is C₁-C₆ alkyl, halogen, or aryl; Cyc is C₃ or C₄ cycloalkyl; p is 0-3 for Cyc being C₄ cycloalkyl, or p=0-2 for Cyc being C₃ cycloalkyl; Y is O, S, or NR, where R═H, alkyl or aryl; X is O, S, NR, or CR³R⁴; Z is H, alkyl, cycloalkyl, aryl or (cyclo)alkylcarbonyl; R¹ is H, alkyl, aryl or O; R² is H, alkyl or aryl; R³ and R⁴ are, independently, H, alkyl or aryl; and n is an integer from 1 to 10; or a pharmaceutically acceptable salt, ester or prodrug thereof.
 20. The method as claimed in claim 19, wherein said disorder or condition is ischemic/reperfusion injury, post myocardial infarction, angina, heart failure, a cardiomyopathy, peripheral vascular disease, diabetes, and lactic acidosis, or symptoms or side effects associated with open heart surgery, bypass surgery, or heart transplant.
 21. The method as claimed in claim 20, wherein said disorder or condition is ischemic/reperfusion injury.
 22. The method as claimed in claim 19, wherein said compound is represented by the Formula (I), and wherein p=0; Y is O; X is N or O; R1, R2, R3 and R4 are hydrogens; n is 1-4; and Z is lower alkyl, cycloalkyl or phenyl.
 23. The method as claimed in claim 19, wherein said compound is represented by the Formula (I), and wherein p=0; Y is N; X is O; R1, R2, R3 and R4 are hydrogens; n is 1 or 2; and Z is hydrogen.
 24. The method as claimed in claim 19, wherein said compound is represented by the Formula (II), wherein p=0.
 25. The method as claimed in claim 19, wherein said at least one compound is selected from the group consisting of cyclopropanecarboxylic acid; cyclobutanecarboxylic acid; cyclopropanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester; cyclobutanecarboxylic acid, 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester; (cyclobutanecarbonyl-amino)-acetic acid; cyclopropanecarboxylic acid, 2-(2-benzyloxy-ethoxy)-ethyl ester; 2-(cyclopropanecarbonyl-amino)-propionic acid; cyclobutanecarboxylic acid 2-(2-benzyloxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-butoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-dimethylamino-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-hexyloxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-methoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester; cyclobutanecarboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid 2-isopropoxy-ethyl ester; cyclobutanecarboxylic acid 2-isopropoxy-ethyl ester; cyclopropanecarboxylic acid, 2-(2-cyclobutanecarbonyloxy-ethoxy)-ethyl ester; cyclopropanecarboxylic acid, 2-[2-(2-cyclopropanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester; and cyclobutanecarboxylic acid, 2-[2-(2-cyclobutanecarbonyloxy-ethoxy)-ethoxy]-ethyl ester.
 26. A kit containing a pharmaceutical composition as claimed in claim
 6. 27. The kit as claimed in claim 26, wherein said kit comprises a label or packaging insert containing instructions for use, in vitro, in vivo, or ex vivo, of components of said kit. 